6-O-substituted bicyclic ketolides

ABSTRACT

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof:                    
     which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

REFERENCE TO RELATED APPLICATIONS

This application is related to commonly assigned U.S. patent applicationSer. Nos. 10/455,219, 10/455,648 and 10/455,001, filed on even dateherewith.

TECHNICAL FIELD

The present invention relates to novel semisynthetic macrolides havingantibacterial activity and which are useful in the treatment andprevention of bacterial infections. More particularly, the inventionrelates to 11,12-cyclized erythromycin derivatives, compositionscontaining such compounds and methods for using the same, as well asprocesses for making such compounds.

BACKGROUND OF THE INVENTION

Erythromycins A through D, represented by formula (E) as illustratedbelow,

Erythromycin R^(a) R^(b) A —OH —CH₃ B —H —CH₃ C —OH —H D —H —H

are well-known and potent antibacterial agents, used widely to treat andprevent bacterial infection. As with other antibacterials, however,bacterial strains having resistance or insufficient susceptibility toerythromycin have been identified. Also, erythromycin A has only weakactivity against Gram-negative bacteria. Therefore, there is acontinuing need to identify new erythromycin derivative compounds whichpossess improved antibacterial activity, which have less potential fordeveloping resistance, which possess the desired Gram-negative activity,or which possess unexpected selectivity against target microorganisms.Consequently, numerous investigators have prepared chemical derivativesof erythromycin in an attempt to obtain analogs having modified orimproved profiles of antibiotic activity.

Kashimura et al. have disclosed 6-O-methylerythromycin derivativeshaving a tricyclic basic nuclear structure in European Application559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed5-O-desoaminylerythronolide derivatives containing a tricyclic carbamatestructure in PCT Application WO 93/21200, published Apr. 22, 1992.

Recently erythromycin derivatives containing a variety of substituentsat the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549,6,075,011 and 6,420,555 B1 as well as PCT Applications WO 00/78773 andWO 03/024986. Furthermore, Ma et. al. have described erythromycinderivatives with aryl groups tethered to the C-6 position in J. MedChem., 44, pp 4137-4156 (2001).

More recently, erythromycin derivatives containing a lactone moiety atthe C11-C12 position have been disclosed in PCT Application WO 02/16380,published Feb. 28, 2002 as well as WO 02/50091 and WO 02/50092, bothpublished Jun. 27, 2002 and WO 03/024986, which published Mar. 27, 2003.

SUMMARY OF THE INVENTION

The present invention provides a novel class of C11-C12 cyclizederythromycin compounds that possess antibacterial activity.

In one aspect of the present invention there are disclosed novelbicyclic erythromycin compounds represented by formula I as illustratedbelow:

as well as the pharmaceutically acceptable salts, esters and prodrugsthereof.

In formula I:

A is selected from:

(a) —OH;

(b) —OR_(p), where R_(p) is a hydroxy protecting group;

(c) —R₁, where R₁ is selected from:

1. aryl;

2. substituted aryl;

3. heteroaryl; and

4. substituted heteroaryl;

(d) —OR₁, where R₁ is as previously defined;

(e) —R₂, where R₂ is selected from:

1. hydrogen;

2. halogen;

3. C₁-C₆ alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sand N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

4. C₂-C₆ alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sand N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; and

5. C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sand N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

(f) —OR₂, where R₂ is previously defined;

(g) —S(O)_(n)R₁₁, where n=0, 1 or 2, and R₁₁ is selected from hydrogen,R₁ and R₂, where R₁ and R₂ are as previously defined;

(h) —OC(O)R₁₁, where R₁₁ is as previously defined;

(i) —C(O)R₁₁, where R₁₁ is as previously defined;

(j) —C(O)NHR₁₁, where R₁₁ is as previously defined;

(k) —OC(O)NHR₁₁, where R₁₁ is as previously defined;

(l) —NHC(O)R₁₁, where R₁₁ is as previously defined;

(m) —NHC(O)NHR₁₁, where R₁₁ is as previously defined;

(n) —NHS(O)_(n)R₁₁, where n and R₁₁ are as previously defined;

(o) —NR₁₄R₁₅, where R₁₄ and R₁₅ are each independently R_(11,) where R₁₁is as previously defined; and

(p) —NHR₃, where R₃ is an amino protecting group;

B is selected from:

(a) hydrogen;

(b) deuterium;

(c) —CN;

(d) —NO₂;

(e) halogen;

(f) —OH;

(g) —R₁, where R₁ is as previously defined;

(h) —R₂, where R₂ is as previously defined; and

(i) —OR_(p), where R_(p) is as previously defined;

provided that when B is halogen, —NO₂, —OH or OR_(p), A is R₁ or R₂;

or, alternatively, A and B taken together with the carbon atom to whichthey are attached are selected from:

(a) C═O;

(b) C(OR₂)₂, where R₂ is as previously defined;

(c) C(SR₂)₂, where R₂ is as previously defined;

(d) C(OR₁₂)(OR₁₃), where R₁₂ and R₁₃ taken together are —(CH₂)_(m)—, andwhere m is 2 or 3;

(e) C(SR₁₂)(SR₁₃), where R₁₂ and R₁₃ taken together are —(CH₂)_(m),where m is as previously defined;

(f) C═CR₁₁R₁₄, where R₁₁ and R₁₄ are as previously defined;

(g) C═N—O—R₁₁, where R₁₁ is as previously defined;

(h) C═NNHR₁₁, where R₁₁ is as previously defined;

(i) C═NNHC(O)R₁₁, where R₁₁ is as previously defined;

(j) C═NN═CR₁₁R₁₄, where R₁₁ and R₁₄ are as previously defined;

(k) C═NNHC(O)NHR₁₁, where R₁₁ is as previously defined;

(l) C═NNHS(O)_(n)R₁₁, where n and R₁₁ are as previously defined;

(m) C═NNHR₃, where R₃ is as previously defined; and

(n) C═NR₁₁, where R₁₁ is as previously defined;

one of X and Y is hydrogen and the other is selected from:

(a) hydrogen;

(b) deuterium;

(c) —OH;

(d) —OR_(p), where R_(p) is as previously defined; and

(e) —NR₄R₅, where R₄ and R₅ are each independently selected from:

1. hydrogen; and

2. C₁-C₁₂ alkyl, optionally substituted with one or more substituentsselected from halogen, cyano, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; or

R₄ and R₅, taken together with the nitrogen atom to which they areattached form a 3-10 membered heteroalkyl ring containing 0-2 additionalhetero atoms selected from the group consisting of O, S and N; or

alternatively, X and Y taken together with the carbon atom to which theyare attached are selected from:

(a) C═O;

(b) C═NR₁₁, where R₁₁ is as previously defined;

(c) C═NC(O)R₁₁, where R₁₁ is as previously defined;

(d) C═N—OR₆, where R₆ is selected from:

1. hydrogen;

2. —CH₂O(CH₂)₂OCH_(3.)

3. —CH₂O(CH₂O)_(n)CH_(3,) where n is as previously defined;

4. —C₁-C₁₂ alkyl, optionally substituted with one or more substituentsselected from halogen, cyano, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl;

5. C₃-C₁₂ cycloalkyl;

6. C(O)—C₁-C₁₂ alkyl;

7. C(O)—C₃-C₁₂ cycloalkyl;

8. C(O)—R₁, where R₁ is as previously defined; and

9. —Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are eachindependently selected from C₁-C₁₂ alkyl, aryl and substituted aryl; and

(e) C═N—O—C(R₇)(R₈)—O—R₆, where R₆ is as previously defined, providedthat R₆ is not C(O)—C₁-C₁₂ alkyl, C(O)—C₃-C₁₂ cycloalkyl, or C(O)—R₁;and R₇ and R₈ taken together with the carbon atom to which they areattached form a C₃-C₁₂ cycloalkyl group or each is independentlyselected from:

1. hydrogen; and

2. C₁-C₁₂ alkyl;

L is selected from:

(a) —CH(OH)CH₃;

(b) C₁-C₆ alkyl, optionally substituted with one or more substituentsselected from halogen, cyano, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

(c) C₂-C₆ alkenyl, optionally substituted with one or more substituentsselected from halogen, cyano, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; and

(d) C₂-C₆alkynyl, optionally substituted with one or more substituentsselected from halogen, cyano, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

W is selected from:

(a) C₂-C₆ alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sand N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

(b) C₂-C₆ alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O,S and N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; and

(c) C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O,S and N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl;

Z is selected from:

(a) hydrogen;

(b) halogen; and

(c) C₁-C₆alkyl, optionally substituted with one or more subtstitnientsselected from halogen, cyano, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; and

R₂′ is hydrogen or R_(p), where R_(p,) is as previously defined.

In another aspect of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention in combination with apharmaceutically acceptable carrier, and treatment of antibacterialinfections with such compositions. Suitable carriers and methods offormulation are also disclosed. The compounds and compositions of thepresent invention have antibacterial activity.

In a further aspect of the present invention there are providedprocesses for the preparation of 11, 12-cyclized erythromycinderivatives of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the present invention includes compoundsrepresented by formula I, as illustrated above, as well as thepharmaceutically acceptable salts, esters and prodrugs thereof.

A preferred group of compounds of the present invention are thoserepresented by formula I wherein L is ethyl and A, B, W, X, Y, Z and R₂′are as previously defined.

Representative compounds of the invention are those selected from:

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH₂, X andY taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH(O), X andY taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NHCH₂-(4-chlorophenyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-phenyl, X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(2-pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(3-pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(3-quinolyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(2-pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(3quinolyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH-phenyl,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(2-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-(5-cyano)pyridyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(6-(aminocarbonyl)-3-quinolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡C-phenyl),X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(2-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-(5-cyano)pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(3-pyridinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(2-pyrimidyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrazinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(6-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C≡O, Z is H, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡C-phenyl, Xand Y taken together with the carbon atom to which they are attached areC═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C═C-(2-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-(5-cyano)pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrimidyl)-2-thienyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H;

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H;and

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrazinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The terms “C₁-C₃ alkyl,” “C₁-C₆ alkyl,” or “C₁-C₁₂ alkyl,” as usedherein, refer to saturated, straight- or branched-chain hydrocarbonradicals containing between one and three, one and twelve, or one andsix carbon atoms, respectively. Examples of C₁-C₃ alkyl radicals includemethyl, ethyl, propyl and isopropyl radicals; examples of C₁-C₆ alkylradicals include, but are not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals; andexamples of C₁-C₁₂ alkyl radicals include, but are not limited to,ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.

The term “substituted alkyl,” as used herein, refers to a “C₂-C₁₂ alkyl”or “C₁-C₆ alkyl” group as previously defined, substituted by independentreplacement or one, two, or three of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The terms “C₂-C₁₂ alkenyl” or “C₂-C₆ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbondouble bond by the removal of a single hydrogen atom. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, and the like.

The term “substituted alkenyl,” as used herein, refers to a “C₂-C₁₂alkenyl” or “C₂-C₆ alkenyl” group as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The terms “C₂-C₁₂ alkynyl” or “C₂-C₆ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety containing from twoto twelve or two to six carbon atoms having at least one carbon-carbontriple bond by the removal of a single hydrogen atom. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to a “C₂-C₁₂alkynyl” or “C₂-C₆ alkynyl” group as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkenyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C_(1-C) ₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl,—NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy and n-hexoxy.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “substituted aryl,” as used herein, refers to an aryl group, aspreviously defined, substituted by independent replacement or one, two,or three of the hydrogen atoms thereon with substituents including, butnot limited to, —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN,—C₁-C₁₂-alkyl optionally substituted with halogen, C₂-C₁₂-alkenyloptionally substituted with halogen, —C₂-C₁₂-alkynyl optionallysubstituted with halogen, —NH₂, protected amino, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH, —C₃-C₁₂-cycloalkyl,—NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino,-diarylamino, diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH-C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “arylalkyl,” as used herein, refers to a C₁-C₃ alkyl or C₁-C₆alkyl residue attached to an aryl ring. Examples include, but are notlimited to, benzyl, phenethyl and the like.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by independent replacement orone, two, or three of the hydrogen atoms thereon with substituentsincluding, but not limited to, but not limited to, —F, —Cl, —Br, —I,—OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substitutedwith halogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “heteroaryl,” as used herein, refers to a mono-, bi-, ortri-cyclic aromatic radical or ring having from five to ten ring atomsof which one ring atom is selected from S, O and N; zero, one or tworing atoms are additional heteroatoms independently selected from S, Oand N; and the remaining ring atoms are carbon, wherein any N or Scontained within the ring may be optionally oxidized. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “substituted heteroaryl,” as used herein, refers to aheteroaryl group as previously defined, substituted by independentreplacement or one, two, or three of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁—C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl; —NHSO₂C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₃-C₁₂-cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or bicyclic saturated carbocyclic ringcompound by the removal of a single hydrogen atom. Examples include, butnot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

The term “substituted C₃-C₁₂-cycloalkyl,” as used herein, refers to aC₃-C₁₂-cycloalkyl group as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “heterocycloalkyl,” as used herein, refers to a non-aromatic5-, 6- or 7-membered ring or a bi- or tri-cyclic group fused system,where (i) each ring contains between one and three heteroatomsindependently selected from oxygen, sulfur and nitrogen, (ii) each5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0to 2 double bonds, (iii) the nitrogen and sulfur heteroatoms mayoptionally be oxidized, (iv) the nitrogen heteroatom may optionally bequaternized, and (iv) any of the above rings may be fused to a benzenering. Representative heterocycloalkyl groups include, but are notlimited to, [1,3]dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, andtetrahydrofuryl.

The term “substituted heterocycloalkyl,” as used herein, refers to aheterocycloalkyl group, as previously defined, substituted byindependent replacement or one, two, or three of the hydrogen atomsthereon with substituents including, but not limited to, —F, —Cl, —Br,—I, —OH, protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionallysubstituted with halogen, C₂-C₁₂-alkenyl optionally substituted withhalogen, —C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂,protected amino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl,—NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroalkyl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₁-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃—C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃-C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “heteroarylalkyl,” as used herein, refers to a C₁-C₃ alkyl orC₁-C₆ alkyl residue residue attached to a heteroaryl ring. Examplesinclude, but are not limited to, pyridinylmethyl, pyrimidinylethyl andthe like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement or one, two, or three of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —C₁-C₁₂-alkyl optionally substituted withhalogen, C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂-C₂C₁₂-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,-methoxymethoxy, -methoxyethoxy, —SH, —S—C₁-C₁₂-alkyl,—S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl, —S—C₃C₁₂-cycloalkyl, —S-aryl,—S-heteroaryl, —S-heterocycloalkyl, or methylthiomethyl.

The term “C₁-C₆ alkoxy,” as used herein, refers to a C₁-C₆ alkyl group,as previously defined, attached to the parent molecular moiety throughan oxygen atom. Examples of C₁-C₆-alkoxy include, but are not limitedto, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy,neopentoxy and n-hexoxy.

The term “C₁-C₃-alkyl-amino,” as used herein, refers to one or twoC₁-C₃-alkyl groups, as previously defined, attached to the parentmolecular moiety through a nitrogen atom. Examples of C₁-C₃-alkyl-aminoinclude, but are not limited to, methylamino, dimethylamino, ethylamino,diethylamino, and propylamino.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl)(C₁-C₁₂ alkyl), where C₁-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, dimethylamino,diethylamino, methylethylamino, piperidino, and the like.

The term “alkoxycarbonyl” represents an ester group, i.e., an alkoxygroup, attached to the parent molecular moiety through a carbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl, and the like.

The term “carboxaldehyde,” as used herein, refers to a group of formula—CHO.

The term “carboxy,” as used herein, refers to a group of formula —COOH.

The term “carboxamide,” as used herein, refers to a group of formula—C(O)NH(C₁-C₁₂ alkyl) or —C(O)N(C₁-C₁₂ alkyl)(C₁-C₁₂ alkyl), —C(O)NH₂,and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) edition, John Wiley & Sons, New York(1999). Examples of hydroxy protecting groups include, but are notlimited to, methylthiomethyl, tert-butyl-dimethylsilyl,tert-butyldiphenylsilyl, acyl substituted with an aromatic group and thelike.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, andthe like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4^(th) ed., edited by John A. Riddick et al., Vol. II, inthe Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4^(th) ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

“An effective amount,” as used herein, refers to an amount of a compoundwhich confers a therapeutic effect on the treated subject. Thetherapeutic effect may be objective (i.e., measurable by some test ormarker) or subjective (i.e., subject gives an indication of or feels aneffect). An effective amount of the compound described above may rangefrom about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 toabout 50 mg/Kg. Effective doses will also vary depending on route ofadministration, as well as the possibility of co-usage with otheragents.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as I- or (S)-, or as (D)- or (L)- for amino acids. Thepresent invention is meant to include all such possible isomers, as wellas their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. The configuration ofany carbon-carbon double bond appearing herein is selected forconvenience only and is not intended to designate a particularconfiguration unless the text so states; thus a carbon-carbon doublebond or carbon-heteroatom double bond depicted arbitrarily herein astrance may be cis, trans, or a mixture of the two in any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the an such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the compounds of this invention, including the compoundsof formulae described herein, are defined to include pharmaceuticallyacceptable derivatives or prodrugs thereof. A “pharmaceuticallyacceptable derivative or prodrug” means any pharmaceutically acceptablesalt, ester, salt of an ester, or other derivative of a compound of thisinvention which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention.

When the compositions of this invention comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “protozoa infections”; includes, but is not limited to,bacterial infections and protozoa infections that occur in mammals, fishand birds as well as disorders related to bacterial infections andprotozoa infections that may be treated or prevented by administeringantibiotics such as the compounds of the present invention. Suchbacterial infections and protozoa infections and disorders related tosuch infections include, but are not limited to, the following:pneumonia, otitis media, □herefore, bronchitis, tonsillitis, andmastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, orPeptostreptococcus spp. Pseudomonas spp.; pharynigitis, rheumatic fever,and glomerulonephritis related to infection by Streptococcus pyogenes,Groups C and G streptococci, Clostridium diptheriae, or Actinobacillushaemolyticum; respiratory tract infections related to infection byMycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae,Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin andsoft tissue infections, abscesses and osteomyelitis, and puerperal feverrelated to infection by Staphylococcus aureus, coagulase-positivestaphylococci (i.e., S. epidermidis, S. homolyticus, etc.), S. pyogenes,S. agalactiae, Streptococcal groups C-F (minute-colony streptococci),viridans streptococci, Corynebacterium spp., Clostridium spp., orBartonella henselae; uncomplicated acute urinary tract infectionsrelated to infection by S. saprophyticus or Enterococcus spp.;urethritis and cervicitis; and sexually transmitted diseases related toinfection by Chlamydia trachomatis, Haemophilus ducreyi, Treponemapallidum, Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseasesrelated to infection by S. aureus (food poisoning and Toxic shocksyndrome), or Groups A, S, and C streptococci; ulcers related toinfection by Helicobacter pylori; systemic febrile syndromes related toinfection by Borrelia recurrentis; Lyme disease related to infection byBorrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitisrelated to infection by C. trachomatis, N. gonorrhoeae, S. aureus, S.pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminatedMycobacterium avium complex (MAC) disease related to infection byMycobacterium avium, or Mycobacterium intracellulare; gastroenteritisrelated to infection by Campylobacter jejuni; intestinal protozoarelated to infection by Cryptosporidium spp. Odontogenic infectionrelated to infection by viridans streptococci; persistent cough relatedto infection by Bordetella pertussis; gas gangrene related to infectionby Clostridium perfringens or Bacteroides spp.; Skin infection by S.aureus, Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Bacterial infections and protozoa infections and disorders related tosuch infections that may be treated or prevented in animals include, butare not limited to, the following: bovine respiratory disease related toinfection by P. haemolytica., P. multocida, Mycoplasma bovis, orBordetella spp.; cow enteric disease related to infection by E. coli orprotozoa (i.e., □herefore, cryptosporidia, etc.), dairy cow mastitisrelated to infection by S. aureus, S. uberis, S. agalactiae, S.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuropneumoniac.,P. multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella spp., orSerpulina hyodyisinteriae; cow footrot related to infection byFusobacterium spp.; cow metritis related to infection by E. coli; cowhairy warts related to Infection by Fusobacterium necrophorum orBacteroides nodosus; cow pink-eye related to infection by Moraxellabovis, cow premature abortion related to infection by protozoa (i.e.neosporium); urinary tract infection in dogs and cats related toinfection by E. coli; skin and soft tissue infections in dogs and catsrelated to infection by S. epidermidis, S. intermedius, coagulase neg.Staphylococcus or P. multocida; and dental or mouth infections in dogsand cats related to infection by Alcaligenes spp., Bacteroides spp.,Clostridium spp., Enterobacter spp., Eubacterium spp.,Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plas,odium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., and Trichomonas spp. Or Prevotella spp. Other bacterialinfections and protozoa infections and disorders related to suchinfections that may be treated or prevented in accord with the method ofthe present invention are referred to in J. P. Sanford at al., “TheSanford Guide To Antimicrobial Therapy,” 26^(th) Edition, (AntimicrobialTherapy, Inc., 1996).

Antibacterial Activity

Susceptibility tests can be used to quantitatively measure the in vitroactivity of an antimicrobial agent against a given bacterial isolate.Compounds were tested for in vitro antibacterial activity by amicro-dilution method. Minimal Inhibitory Concentration (MIC) wasdetermined in 96 well microliter plates utilizing the appropriateMueller Hinton Broth medium (CAMHB) for the observed bacterial isolates.Antimicrobial agents were serially diluted (2-fold) in DMSO to produce aconcentration range from about 64 μg/ml to about 0.03 μg/ml. The dilutedcompounds (2 μl/well) were then transferred into sterile, uninoculatedCAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculumfor each bacterial strain was standardized to 5×10⁵ CFU/mL by opticalcomparison to a 0.5 McFarland turbidity standard. The plates wereinoculated with 10 μl/well of adjusted bacterial inoculum. The 96 wellplates were covered and incubated at 35+/−2° C. for 24 hours in ambientair environment. Following incubation, plate wells were visuallyexamined by Optical Density measurement for the presence of growth(turbidity). The lowest concentration of an antimicrobial agent at whichno visible growth occurs was defined as the MIC. The compounds of theinvention generally demonstrated an MIC in the range from about 64 μg/mlto about 0.03 μg/ml.

All in vitro testing follows the guidelines described in the ApprovedStandards M7-A4 protocol, published by the National Committee forClinical Laboratory Standards (NCCLS).

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and I) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention,bacterial infections are treated or prevented in a patient such as ahuman or other animals by administering to the patient a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant a sufficient amount of the compound to treat bacterialinfections, at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particularpatient will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; the activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or contemporaneously with the specific compound employed;and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the formulae described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparations maycontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

The pharmaceutical compositions of this invention can be administeredorally to fish by blending said pharmaceutical compositions into fishfeed or said pharmaceutical compositions may be dissolved in water inwhich infected fish are placed, a method commonly referred to as amedicated bath. The dosage for the treatment of fish differs dependingupon the purpose of administration (prevention or cure of disease) andtype of administration, size and extent of infection of the fish to betreated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kgof body weight of fish may be administered per day, either at one timeor divided into several times. It will be recognized that theabove-specified dosage is only a general range which may be reduced orincreased depending upon the age, body weight, condition of disease,etc. of the fish.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety

Abbreviations

Abbreviations which may be used in the descriptions of the schemes andthe examples that follow are: Ac for acetyl; AIBN for2,2-azobisisobutyronitrile; Bn for benzyl; Boc for t-butoxycarbonyl;Bu₃SnH for tributyltin hydride; Bz for benzoyl; CDI forcarbonyldiimidazole; dba for dibenzylidene acetone; dppb fordiphenylphosphino butane; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;DCC for 1,3-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate;DIBAL-H for diisopropyl aluminum hydride; DIC for1,3-diisopropylcarbodiimide; DIEA for diisopropylethylamine; DMAP fordimethylaminopyridine; DMF for dimethyl formamide; DMSO fordimethylsulfoxide; DPPA for diphenylphosphoryl azide; LAH for lithiumaluminum hydride; EtoAc for ethyl acetate; KHMDS for potassiumbis(trimethylsilyl)amide; LDA for lithium diisopropyl amide; MeOH formethanol; Me₂S for dimethyl sulfide; MOM for methoxymethyl; OMs formesylate; OTos for tosylate; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NCS for N-chlorosuccinimide; NMMO for4-methylmorpholine N-oxide; PCC for pyridinium chlorochromate; PDC forpyridinium dichromate; Ph for phenyl; POPd for dihydrogendichlorobis(di-tert-butylphosphino)palladium(II); TFA for triethylamine;THF for tetrahydrofuran; TPP or PPh₃ for triphenylphosphine; TBS fortert-butyl dimethylsilyl; and TMS for trimethylsilyl.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes which areillustrative of the methods by which the compounds of the invention maybe prepared. The groups A, B, W, X, Y, Z, R₂′, R₄″ and R₁₁ are aspreviously defined unless otherwise noted below.

A process of the invention for the preparation of compounds of formulaI, as illustrated in Scheme 1, involves preparing compounds of formula(1.4) and (1.5) by a tandem radical or anionic addition and cyclizationof compounds of formula (1.2) or (1.3).

Intermediates (1.2) and (1.3) can be prepared by alkylation of thereadily available compounds of formula (1.1) which can be preparedaccording to the process described by Baker et al. J. Org. Chem. 1988,53, 2340-2345; Elliott et al. J. Med. Chem. 1988, 41, 1651-1659; Ma etal. J. Med. Chem. 2001, 44, 4137-4156, and Or et al. U.S. Pat. No.6,075,011-B1. Typical alkylating conditions include treating compoundsof formula (1.1) with a suitable alkylating agent, such as propargylhalide, allyl halide, allyl mesylate or the like, in the presence of abase such as K₂CO₃, NaOH, NaH, LDA or the like, optionally with a phasetransfer catalyst such as tetrabutylammonium iodide, 18-crown-6 or thelike, in THF, toluene, methylene chloride, DMF, DMSO, water or the like,or combinations thereof, at from about −50° C. to about 100° C. for 1hour to 24 hours to provide compounds of formula (1.2) and (1.3).Alternatively, compounds of formula (1.3) can be obtained by reaction ofa suitable alkylating agent such as tert-butyl allyl carbonate,tert-butyl 2-butenyl carbonate, allyl acetate, allyl benzoate or thelike, in the presence of a palladium catalyst, such as palladium(II)acetate, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),tetra(dibenzylidenacetone)dipalladium(0), palladium on carbon or thelike, and a suitable phosphine ligand, such as triphenylphosphine,bis(diphenylphosphino)methane, 1,2-bis(diphenyl phosphino)ethane,1,3-bis(diplienylphosphino)propane, 1,4-bis(diphenylphosphino)butane,tri-o-tolyl-phosphine, or the like, in an aprotic solvent, such astetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide,N-methyl-2-pyrrolidinone, hexamethylphosphoric triamide,1,2-dimethoxyethane, methyl-tert-butyl ether, heptane, acetonitrile,acetonitrile and ethyl acetate or the like, at from 40° C. to about 150°C. for 0.5 hour to about 48 hours.

In accordance with Scheme 1, compounds of formula I (1.4) and (1.5) ofthe present invention can be prepared by methods which are well known inthe art involving a tandem radical addition and cyclization ofintermediates (1.2) and (1.3) with a suitable radical species (R.) whichcan be generated from a radical precursor and an initiator. The radicalR. can be centered as, but not limited to, carbon, silicon, tin, oxygen,sulfur, nitrogen, halogen with non-, mono-, di- or tri-substitutiondepending on the nature of the radical centered atom. A typical radicalof this process is selected from, but not limited to, a group consistingof PhCH₂., Et₃Si, (n-Bu)₃Sn., tert-BuO., AcS., PhCH₂CH₂S. and Br.. Atypical radical precursor for this process is selected from, but notlimited to, C₁-C₁₂ alkyl halide, C₂-C₆ alkenyl halide, C₂-C₆ alkynylhalide, C₂-C₆ alkenyl tri(C₁-C₁₂ alkyl)stannane, tri(C₁-C₁₂alkyl)stannane, hexamethyldistannane, trichlorosilane, triphenylsilane,tert-butyl hydrogen peroxide, thiolacetic acid, phenyl disulfide,N-bromosuccinamide and bromine. A typical radical initiator of thisprocess can be selected from, but not limited to, a group consisting ofAIBN, tert-butyl peroxide, benzoyl peroxide. The preferred radicalreaction conditions of the present invention includes reacting thecompounds of formula (1.2) or (1.3) with a radical generated from agroup consisting of, but not limited to, halide, stannane, distannane,silane, mercaptan or disulfide, in the presence of AIBN, optionally inthe presence of a reducing agent such as tributylstannane,diphenylsilane, sodium borohydride, magnesium, lithium aluminum hydrideor the like, at 40° C. to 150° C. for a period of from 1 hour to 10days, in an aprotic solvents, such as tetrahydrofuran,N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidinone,1,2-dimethioxyethane, methyl-tert-butyl ether, cyclohexane, heptane,acetonitrile, benzene, toluene and ethyl acetate or the like.

Alternatively compounds of formula I (1.4) of the present invention maybe prepared by a tandem anionic addition and cyclization ofintermediates (1.2) with a suitable anionic species (R⁻) which can begenerated from an organometallic precursor. Typically a compound offormula (1.2) is reacted with an organometallic reagents, such asallylmagnesium chloride, methylmagnesium iodide, phenyllithium,triethylaluminum, triethoxysilane, or the like, in the presence of0-100% molar percent (relative to compound 1.2) of a transitional metalor its salt or its complex such as palladium, iridium, chromium(III)chloride, cerium(III) chloride, palladium(II) acetate, platinum(II)chloride, chloroplatinic acid, nonacahonyliron(0), titanocene(IV)dichloride, bis(1,5-cyclooctadiene)nickel(0),tetrakis(triphenylphosphine)palladium(0) or the like, at −78° C. to 100°C. for a period of from 0.5 to 48 hours, in an aprotic solvents, such astetrahydrofuran, dimethyl sulfoxide, N-methyl-2-pyrrolidinone,1,2-dimethoxyethane, methyl-tert-butyl ether, cyclohexane, heptane,acetonitrile, benzene and toluene or the like.

Another process of the invention involves the removal of the cladinosemoiety of the compounds of formula I. The cladinose moiety of themacrolide compounds of formulae (1.4) and (1.5) can be removed to givecompounds of formulae (1.6) and (1.7) in Scheme 1 by a dilute acid, suchas hydrochloric acid, sulfuric acid, perchloric acid, nitric acid,chloroacetic acid, dichloroacetic acid, trifluoroacetic acid andp-toluenesulfonic acid or the like, in a suitable solvent, such asmethanol, ethanol, isopropanol, butanol, water or the like, or themixtures thereof, at 0° C. to about 80° C. for 0.5 hour to 24 hours.

When R₂″ is an acyl protecting group, it can be removed upon treatmentwith methanol at from room temperature to 60° C. When R₂″ is a silylprotecting group, the deprotection can be also effected by an acid, suchas dilute hydrochloric acid, sulfuric acid, perchloric acid, nitricacid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid andp-toluenesulfonic acid or the like, or a fluoride, such astetrabutylammonium fluoride, pyridinium fluoride, ammonium fluoride,hydrofluoric acid or the like, at from 0°C. to 50° C. for 0.5 to 24hours.

Compounds according to the invention (2.1) and (2.2) may be prepared byoxidation of the secondary alcohol using Dess-Martin periodinane as theoxidant. The reaction is typically run in an aprotic solvent at 0° to25° C. for 0.5 to 12 hours.

Alternatively the oxidation can be accomplished using pyridiniumchlorochromate, sulfur trioxide pyridine complex in dimethyl sulfoxide,tetra-n-propyl ammonium perruthenate and N-methyl morpholine N-oxide,Swern oxidation or the like. A more thorough discussion of the oxidationof secondary alcohols can be found in M. B. Smith and J. March “AdvancedOrganic Chemistry” 5^(th) ed., Wiley & Son, Inc, 2001, which is herebyincorporated by reference herein.

Conversion of the alkene of formula (3.1) into the ketone (3.2) can beaccomplished by exposure of the alkene to ozone followed bydecomposition of the ozonide intermediate with an appropriate reducingagent, as outlined in Scheme 3. The reaction is typically carried out ina solvent such as, for example, methanol, ethanol, ethyl acetate,glacial acctic acid, chloroform, methylene chloride or hexanes, ormixtures thereof, at from −78° C. to −20° C. Representative reducingagents include, for example, triphenylphosphine, trimethyl phosphite,thiourea, and dimethyl sulfide or the like. A more thorough discussionof ozonolysis and the conditions therefore can be found in M. B. Smithand J. March “Advanced Organic Chemistry” 5^(th) ed., Wiley & Son, Inc,2001.

An alternative method for the preparation of the ketones (3.2) involvesdihydroxylation of the alkene followed by diol cleavage. The glycol(3.3) is prepared by reacting the alkene (3.1), either withstoichiometric amounts of osmium tetrdoxide, or with catalytic amountsof osmium tetraoxide if an oxidant such as hydrogen peroxide, tert-butylhydroperoxide, or N-methylmorpholine-N-oxide is present, in a variety ofsolvents such as 1,4-dioxane, tetrahydrofuran, tert-butanol, acetone,dimethyl ether, water or the like, or the mixture thereof, preferably atfrom 0° C. to 50° C.

The glycol (3.3) can be cleaved by a variety of reagents including, butnot limited to, periodic acid, lead tetraacetate, manganese dioxide,potassium permanganate, sodium metaperiodate, and N-iodosuccinamide in avariety of solvents such as 1,4-dioxane, tetrahydrofuran, tert-butanol,acetone, ethanol, methanol, water or the like, or the mixture thereof,at from 0° C. to 50° C.

The synthesis of the ketone (3.2) can also be realized in one-pot byreacting the alkene (3.1) with either stoichiometric amounts orcatalytic amounts of osmium tetraoxide and a glycol cleavage reagent,such as, for example, periodic acid, lead tetraacetate, manganesedioxide, potassium permanganate, sodium metaperiodate, andN-iodosuccinamide or the like, in a solvent such as 1,4-dioxane,tetrahydrofuran, tert-butanol, acetone, ethanol, methanol, water or thelike, or mixtures thereof, at from 0° C. to 50° C.

Compounds of formula (3.2) represent useful intermediates which can befurther functionalized in a variety of ways. Scheme 4 details proceduresfor the conversion of the ketone (3.2) into an oxime of formula (4.1) oran amine of formula (4.2). The formation of oxime (4.1) can beaccomplished under either acidic or basic conditions in a variety ofsolvents such as, for example, methanol, ethanol, water,tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, or mixturesthereof, at from 0° C. to 70° C. over a period of 10 minutes to 12hours. Representative acids include, but are not limited to,hydrochloric acid, phosphoric acid, sulfuric acid, p-toluenesulfonicacid, acetic acid and pyridinium p-toluenesulfonate. Bases which areuseful are, for example, triethylamine, pyridine, diisopropylethylamine, 2,6-lutidine, imidazole and potassium carbonate, and the like.The formation of amines (4.2) can be accomplished by reacting a ketone(3.2) with a primary or secondary amine and a suitable reducing agentsuch as, for example, hydrogen, sodium borohydride, sodiumcyanoborohydride, LAH, zinc, DIBAL-H, triethylsilane, ammonium formateand the like, optionally in the presence of a catalyst such as Raney Ni,palladium on carbon, platinum dioxide,tetrakis(triphenylphosphine)palladium and the like in a suitable solventsuch as methanol, acetonitrile, water, tetrahydrofuran,1,2-dimethoxyethane, ethyl acetate, acetic acid, trifluoroacetic acid,hydrochloric acid or the like, or mixtures thereof, at a pH between 3and 5 over a period of 5 minutes to 24 hours.

Scheme 5 illustrates the procedure by which compounds of formula (5.1)may be converted to compounds of formula (5.2) by treatment with ahalogenating reagent in a suitable solvent such as dimethylformamide,dimethyl sulfoxide, pyrrolidinone and the like. By the process disclosedin U.S. Pat. No. 6,124,269 and International Patent WO 00/62783, whichare hereby incorporated by reference herein in their entirety. Thisreagent acts to replace a hydrogen atom with a halogen atom at the C-2position of the ketolide. Various halogenating reagents may be suitablefor this procedure.

Fluorinating reagents include, but are not limited to,N-fluorobenzenesulfonimide in the presence of base, 10% F₂ in formicacid, 3,5-dichloro-1-fluoropyridinium tetrafluoroborate,3,5-dichloro-1-fluoropyridinium triflate, (CF₃SO₂)₂NF,N-fluoro-N-methyl-p-toluenesulfonamide in the presence of base,N-fluoropyridinium triflate, N-fluoroperfluoropiperidine in the presenceof base. Chlorinating reagents include, but are not limited to,hexachloroethane in the presence of base, CF₃CF₂CH₂Icl₂, SO₂Cl₂, SOCl₂,CF₃SO₂Cl in the presence of base, Cl₂, NaOCl in the presence of aceticacid. Brominating reagents include, but are not limited to,Br₂.pyridine.HBr, Br₂/acetic acid, N-bromosuccinimide in the presence ofbase, LDA/BrCH₂CH₂Br, or LDA/CBr₄. A suitable iodinating reagent isN-Iodosuccinimide in the presence of base, or I₂, for example. Apreferred halogenating reagent is N-fluorobenzesulfonimide in thepresence of sodium hydride.

Suitable bases for the halogenating reactions requiring them arecompounds such as alkali metal hydrides, such as NaH and KH, or aminebases, such as LDA or triethylamine, for example. Different reagents mayrequire different type of base, but this is well known within the art.

It will be appreciated by one skilled in the art that compounds offormula (5.2) can be substituted for compounds of formula (3.1) or (3.2)in the preceding examples if the corresponding C-2 halogenated productis desired.

EXAMPLES

The compounds and processes of the present invention will be describedfurther in detail with respect to specific preferred embodiments by wayof examples, it being understood that these are intended to beillustrative only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH₃W is CH₂CH═CH₂, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is H, and R₂′ is H.

Step 1a. Compound 1.2 of Scheme I: W is CH₂CH═CH₂, R₁₁ is H, R₂′ isC(O)CH₃ and R₄″ is C(O)CH₃.

A mixture of2′,4″-bis-O-acetyl-6-O-allyl-11-deoxy-10,11-didehydroerythromycin (640mg, 0.76 mmol), tetrabutylammonium iodide (56 mg, 0.15 mmol), methylenechloride (4.0 mL), propargyl bromide (80% in toluene, 0.68 mL, 6.09mmol) and sodium hydroxide (50% in water, 6.0 mL) was stirred at roomtemperature for 2 hours. The mixture was partitioned (ethtyl acetate andwater). The organic phases were washed with water and brine, dried(Na₂SO₄) and evaporated. The residue was purified by chromatography(silica, hexanes:acetone/95:5 and 3:1) to give 258 mg (39%) of the titlecompound.

MS (ESI) m/z=878 (M+H)⁺.

Step 1b. Compound 1.4 of Scheme 1: W is CH₂CH═CH_(2,) R and R₁₁ takentogether with the carbon atom to which they are attached are CHSnBu₃,R₂′ is C(O)CH₃ and R₄″ is C(O)CH₃.

A solution of the compound from Step 1a (250 mg, 0.28 mmol) in anhydrousbenzene (5.7 mL) was heated to reflux with tributyltin hydride (249 mg,0.85 mmol) in the presence of AIBN (11.5 mg) for 2 hours beforeevaporation. The residue was chromatographed (silica,hexanes:acetone/95:5˜9:1) to give the title compound (163.5 mg, 49%).

MS (ESI) m/z=1168/1170 (M+H)⁺.

Step 1c. Compound 1.6 of Scheme 1: R and R₁₁ taken together with thecarbon atom to which they are attached are C═CH₂, W is CH₂CH═CH₂, andR₂′ is C(O)CH₃.

A solution of the compound from Step 1b (163.5 mg, 0.14 mmol) in ethanol(4.0 mL) was treated with hydrochloric acid (2 M, 4.0 mL) at 60° C. for2 hours before partition (ethyl acetate and saturated NaHCO₃). Theorganic phases were washed with water and brine, dried (Na₂SO₄) andevaporated. The residue was purified by chromatography (silica,hexanes:acetone/95:5˜4:1) to give the title compound (60.3 mg, 63%).

MS (ESI) m/z=680 (M+H)⁺.

¹³C NMR (125 MHz, CDCl₃): δ 215.7, 174.7, 145.8, 136.4, 116.3, 112.1,100.1, 86.2, 81.1, 79.7, 77.6, 77.4, 71.6, 70.7, 68.8, 64.6, 63.5, 48.7,45.4, 44.3, 40.6, 37.3, 36.5, 35.9, 31.3, 22.0, 21.1, 20.4, 19.5, 15.5,15.3, 14.8, 10.5, 8.1.

Step 1d. Compound I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH₂, X andY taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is C(O)CH₃

Into a solution of the compound from Step 1c (60.3 mg, 0.089 mmol) indichloromethane (3.0 mL) was added Dess-Martin periodinane (56.4 mg,0.13 mmol) at room temperature. The mixture was stirred at roomtemperature for 3.5 hours before additional Dess-Martin periodinane (60mg, 0.14 mmol) was added. The solution was stirred at room temperaturefor another 1.5 hours and then partitioned with ethyl acetate andsaturated sodium bicarbonate-saturated sodium thiosulfate (3:1). Theorganic phases were washed with water and brine, dried (Na₂SO₄) andevaporated before chromatography (silica, hexanes:acetone/95:5˜85:15) togive the title compound (43.8 mg, 73%).

MS (ESI) m/z=678 (M+H)⁺.

¹³C NMR (125 MHz, CDCl₃): δ 215.4, 206.1, 169.9, 169.7, 145.4, 136.2,116.4, 112.0, 100.3, 85.9, 78.8, 78.7, 75.1, 71.3, 70.5, 68.9, 64.3,63.4, 50.6, 48.5, 45.1, 44.3, 40.6, 37.6, 36.1, 30.6, 22.1, 21.3, 21.0,20.3, 19.5, 15.7, 14.8, 12.4, 10.5.

Step 1e. Compound I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH₃, W is CH₂CH═CH₂, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is H, and R₂′ is H.

A solution of the compound from Step 1d (6.5 mg) in methanol (2 mL) wasrefluxed for 2 hours and then evaporated to give the title compound (6.0mg, 98%) as one of the C10 stereoisomers.

MS (ESI) m/z=636 (M+H)⁺.

Example 2

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH₂, X andY taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H.

Step 2a. Compound 1.6 of Scheme I: R and R₁₁ taken together with thecarbon atom to which they are attached are C═CH₂, W is CH₂CH═CH₂, andR₂′ is C(O)CH₃.

A solution of the compound from Step 1b (163.5 mg, 0.14 mmol) in ethanol(4.0 mL) was treated with hydrochloric acid (2 M, 4.0 mL) at 60° C. for2 hours before partition (ethyl acetate and saturated NaHCO₃). Theorganic phases were washed with water and brine, dried (Na₂SO₄) andevaporated. The residue was purified by chromatography (silica,hexanes:acetone/95:5˜4:1) to give the title compound (24.9 mg, 26%).

MS (ESI) m/z=680 (M+H)⁺.

¹³C NMR (125 MHz, CDCl₃): δ 215.8, 176.7, 152.3, 136.3, 115.2, 107.6,104.0, 92.2, 86.1, 80.8, 77.2, 72.1, 69.2, 64.7, 64.6, 61.8, 51.1, 48.4,44.6, 40.8, 39.3, 38.1, 34.8, 29.7, 21.4, 21.2, 20.9, 19.8, 19.6, 15.4,10.9, 10.7, 8.1.

Step 2b. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH₃, W is CH₂CH═CH₂,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is C(O)CH₃

Into a solution of the compound from Step 1c in dichloromethane is addedDess-Martin periodinane at room temperature. The mixture is stirred atroom temperature for 3.5 hours before partition with ethyl acetate andsaturated sodium bicarbonate-saturated sodium thiosulfate (3:1). Theorganic phases are washed with water and brine, dried (Na₂SO₄) andevaporated before chromatography to give the title compound as one ofthe C10 stereoisomers.

Step 2c. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH₂, X and Y taken together with the carbon atom to which they areattached are C═O, Z is H, and R₂′ is H.

A solution of the compound from Step 2b in methanol is refluxed for 2hours and then evaporated to give the title compound as one of the C10stereoisomers.

Example 3

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH₃, W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

Step 3a. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is C(O)CH₃.

A mixture of the compound from Step 1d (30.0 mg, 0.044 mmol),tris(o-toluene)phosphine (10.0 mg, 0.033 mmol), palladium acetate (3.0mg, 0.013 mmol), 3-bromoquinoline (0.015 mL, 0.11 mmol) andtriethylamine (0.10 mL, 0.72 mmol) in acetonitrile (1.5 mL) was degassedand warmed to 70° C. The temperature was kept at 70° C. for 0.5 hourbefore being raised to 100° C. The mixture was kept at this temperaturefor 16 hours before being evaporated. The residue was further purifiedby chromatography (silica, hexanes:acetone/95:5˜1.5:1) to give the titlecompound (12.7 mg, 36%).

MS (ESI) m/z=805 (M+H)⁺.

Step 3b. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

A solution of the compound from Step 3a (12.7 mg) in methanol (2 mL) wasrefluxed for 2 hours and then evaporated. Chromatography (silica,CH₂CH₂:2M NH₃-MeOH/99:1˜97:3) gave the title compound (8.0 mg, 67%).

MS (ESI) m/z=763 (M+H)⁺.

Example 4

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH(O), X andY taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H.

Step 4a. Compound 1.6 of Scheme 1: R and R₁₁ are each H, W is CH₂CH(O)and R₂′ is C(O)CH₃.

To a solution of the compound of Step 1c of Example 1 in aqueous acetoneat 25° C. is added OSO₄ (5 mol %) followed by NaIO₄ (4 equivalents) andthe mixture is stirred for 4-6 hours. The reaction mixture is dilutedwith EtOAc and is washed with aqueous NaHCO₃, brine and dried overNa₂SO₄. Removal of the solvents in vacuo provides the title compound.

Step 4b. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH(O), X and Y taken together with the carbon atom to which they areattached are C═O, Z is H, and R₂′ is C(O)CH₃.

The compound of Step 4a is treated according to the procedure of Step 1dof Example 1 to provide the title compound.

Step 4c. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH(O), X and Y taken together with the carbon atom to which they areattached are C═O, Z is H, and R₂′ is H.

The compound of Step 4b is treated with methanol at 25° C. for 24 hoursor at refluxing temperature for 24 hours. Removal of the solventprovides the title compound.

Example 5

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH₃, W is CH₂C≡CH, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is H, and R₂′ is H.

Step 5a. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is C(O)CH₃.

The compound of Step 4a is treated with an excess of phosphonium Wittigreagent according to the literature procedures ((a.). Tetrahedron Lett.,1999, 40(49), 8575-8578. (b). Synlett., 1996, (6), 521-522.) to providethe title compound.

Step 5b. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C═CH,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is H.

The compound of Step 5a is treated with methanol at 25° C. for 24 hoursor at refluxing temperature for 2-4 hours. Removal of the solventprovides the title compound.

Example 6

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H and R₂′ is H.

A mixture of a compound of Example 5 (1 equivalent) and Pd(PPh₃)₂Cl₂(0.02 equivalents) in 5:1/acetonitrile:triethylamine is degassed andflushed with nitrogen, treated sequentially with CuI (0.01 equivalent)and 3-bromoquinoline (2-3 equivalents), stirred at room temperature for10 minutes, heated at 70° C. for 6-24 hours, diluted with ethyl acetateand washed sequentially with water and brine and dried (Na₂SO₄). Removalof the solvents provides the title compound.

Example 7

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NHCH₂-(4-chlorophenyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H.

To a solution of the compound of Example 4 in methanol is added4-chlorobenzylamine, excess NaBH₃CN and enough acetic acid to give a pH4 at room temperature. The reaction mixture is stirred at roomtemperature for 4-8 hours. The mixture is cooled to 0° C., andneutralized with a solution of saturated aqueous Na2CO₃ and extractedwith CH₂Cl₂. The organic layer is dried over Na₂SO₄. Removal of thesolvents and column chromatography on silica gel provides the titlecompound.

Example 8

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is F, and R₂′ is H.

Step 8a. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is F, and R₂′ is C(O)CH₃.

A solution of the compound of Step 5a of Example 5 in DMF at 0° C. istreated with NaH (2 equivalents) and stirred at 0° C.-room temperaturefor 1 hour followed by addition of (PhSO₂)₂NF (1 equivalent) at 0° C.,and is stirred for 2 hours. The reaction mixture is taken up in ethylacetate and is washed with water, NaHCO₃ and brine and dried overNa₂SO₄. Removal of the solvents provides the title compound.

Step 8b. Compound of formula I: A and B taken together with the carbonatom to which they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is F, and R₂′ is H.

The compound of Step 8a is treated with methanol at 25° C. for 24 hoursor at refluxing temperature for 2-4 hours. Removal of the solventprovides the title compound.

Example 9

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂≡C-(3-quinolyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is F, and R₂′ is H.

A compound of Example 8 is treated according to the procedure of Example6 to provide the title compound.

Examples 10 through 39 may be prepared according to the proceduresdescribed in Examples 3 through 9 and the synthetic schemes anddiscussions contained herein. Example 10

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-phenyl, X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

Example 11

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂(2-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

Example 12

Compound of formula I: A and l taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(3-pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H.

Example 13

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(3quinolyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H.

Example 14

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(2-pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H.

Example 15

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(3-quinolyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H.

Example 16

Compound or formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH-phenyl,X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is H.

Example 17

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(2-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

Example 18

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

Example 19

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-(5-cyano)pyridyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H.

Example 20

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(6-(aminocarbonyl)-3-quinolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H.

Example 21

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is F, and R₂′ is H.

Example 22

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-pyridyl) X and Y taken together with the carbon atom towhich they are attached are C═O, Z is F, and R₂′ is H.

Example 23

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡C-phenyl, Xand Y taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H.

Example 24

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L, is CH₂CH_(3,) W isCH₂C≡C-(2-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is H, and R₂′ is H.

Example 25

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is H, and R₂′ is H.

Example 26

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-(5-cyano)pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is H, and R₂′ is H.

Example 27

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridyl)-2-(thienyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H.

Example 28

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(3-pyridyl)-2-(pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H.

Example 29

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(2-pyrimidyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H.

Example 30

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrazinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H.

Example 31

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(6-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H.

Example 32

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡C-phenyl, Xand Y taken together with the carbon atom to which they are attached areC═O, Z is F, and R₂′ is H.

Example 33

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(2-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is F, and R₂′ is H.

Example 34

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is H, and R₂′ is H.

Example 35

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-(5-cyano)pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H.

Example 36

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is F, and R₂′ is H.

Example 37

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrimidyl)-2-thienyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H.

Example 38

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H.

Example 39

Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrazinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H.

Although the invention has been described in detail with respect tovarious preferred embodiments it is not intended to be limited thereto,but rather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

What is claimed is:
 1. A compound represented by the formula

or a pharmaceutically acceptable salt, ester or prodrug thereof whereinA is selected from: (a) —OH; (b) —OR_(p), where R_(p) is a hydroxyprotecting group; (c) —R₁, where R₁ is selected from;
 1. aryl; 2.substituted aryl;
 3. heteroaryl; and
 4. substituted heteroaryl; (d)—OR₁, where R₁ is as previously defined; (e) —R₂, where R₂ is selectedfrom;
 1. hydrogen;
 2. halogen;
 3. C₁-C₆ alkyl containing 0, 1, 2, or 3heteroatoms selected from O, S and N, optionally substituted with one ormore substituents selected from halogen, cyano, oxo, aryl, substitutedaryl, heteroaryl and substituted heteroaryl;
 4. C₂-C₆ alkenyl containing0, 1, 2, or 3 heteroatoms selected from O, S and N, optionallysubstituted with one or more substituents selected from halogen, cyano,oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and5. C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sand N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl andsubstituted heteoraryl; (f) —OR₂, where R₂ is previously defined; (g)—S(O)₂R₁₁, where n=0, 1 or 2, and R₁₁ is selected from hydrogen, R₁ andR₂, where R₁ and R₂ are as previously defined; (h) —OC(O)R₁₁, where R₁₁is as previously defined; (i) —C(O)R₁₁, where R₁₁ is as previouslydefined; (j) —C(O)NHR₁₁, where R₁₁ is as previously defined; (k)—OC(O)NHR₁₁, where R₁₁ is as previously defined; (l) —NHC(O)R₁₁, whereR₁₁ is as previously defined; (m) —NHC(O)NHR₁₁, where R₁₁ is aspreviously defined; (n) —NHS(O)R₁₁, where n and R₁₁ are as previouslydefined; (o) —NR₁₄R₁₅, where R₁₄ and R₁₅ each independently R_(11,)where R₁₁ is as previously defined; and (p) —NH₃, where R₃ is an aminoprotecting group; B is selected from: (a) hydrogen; (b) deuterium; (c)—CN; (d) —NO₂; (e) halogen; (f) —OH; (g) —R₁, where R₁ is as previouslydefined; (h) —R₂, where R₂ is as previously defined; and (i) —OR_(p),where R_(p) is as previously defined; provided that when B is halogen,—NO₂, —OH or OR_(p), A is R₁ or R₂; or, alternatively, A and B takentogether with the carbon atom to which they are attached are selectedfrom: (a) C═O; (b) C(OR₂)₂, where R₂ is as previously defined; (c)C(SR₂)₂, where R₂ is as previously defined; (d) C(OR₁₂)(OR₁₃), where R₁₂and R₁₃ taken together are —(CH₂)_(m)—, and where m is 2 or 3; (e)C(SR₁₂)(SR₁₃), where R₁₂ and R₁₃ taken together are —(CH₂)_(m), where mis as previously defined; (f) C═CR₁₁R₁₄, where R₁₁ and R₁₄ are aspreviously defined; (g) C═N—O—R₁₁, where R₁₁ is as previously defined;(h) C═NNHR₁₁, where R₁₁ is as previously defined; (i) C═NNHC(O)R₁₁,where R₁₁ is as previously defined; (j) C═NN═CR₁₁R₁₄, where R₁₁ and R₁₄are as previously defined; (k) C═NNHC(O)NHR₁₁, where R₁₁ is aspreviously defined; (l) C═NNHS(O)_(n)R₁₁, when n and R₁₁ are aspreviously defined; (m) C═NNHR₃, where R₃ is as previously defined; and(n) C═NR₁₁, where R₁₁ is as previously defined; one of X and Y ishydrogen and the other is selected from: (a) hydrogen, (b) deuterium;(c) —OH; (d) —OR_(p), where R_(p) is as previously defined; and (e)—NR₄R₅, where R₄ and R₅ are each independently selected from: 1.hydrogen; and
 2. C₁-C₁₂ alkyl, optionally substituted with one or moresubstituents selected from halogen, cyano, aryl, substituted aryl,heteroaryl and substituted heteroaryl; or R₄ and R₅, taken together withthe nitrogen atom to which they are attached form a 3-10 memberedheteroalkyl ring containing 0-2 additional hetero atoms selected fromthe group consisting of O, S and N; or alternatively, X and Y takentogether with the carbon atom to which they are attached are selectedfrom: (a) C═O; (b) C═NR₁₁, where R₁₁ is as previously defined; (c)C═NC(O)R₁₁, where R₁₁ is as previously defined; (d) C═N—OR₆, where R₄ isselected from:
 1. hydrogen;
 2. —CH₂O(CH₂)₂OCH_(3,) 3.—CH₂O(CH₂O)_(n)CH_(3,) where n is as previously defined;
 4. —C₁-C₁₂alkyl, optionally substituted with one or more substituents selectedfrom halogen, cyano, aryl, substituted aryl, heteroaryl and substitutedheteroaryl;
 5. C₃-C₁₂ cycloalkyl;
 6. C(O)—C₁-C₁₂ alkyl;
 7. C(O)—C₃-C₁₂cycloalkyl;
 8. C(O)—R₁, where R₁ is as previously defined; and 9.—Si(R_(a))(R_(b))(R_(c)), wherein R_(a), R_(b) and R_(c) are eachindependently selected from C₁-C₁₂ alkyl, aryl and substituted aryl; and(e) C═N—O—C(R₇)(R₈)—O—R₆, where R₆ is previously defined, provided thatR₆ is not C(O)—C₁-C₁₂ alkyl, C(O)—C₃-C₁₂ cycloalkyl, or C(O)—R₁; and R₇and R₈ taken together with the carbon atom to which they at attachedform a C₃-C₁₂ cycloalkyl group or each is independently selectedfrom:
 1. hydrogen; and
 2. C₁-C₁₂ alkyl; L is selected from: (a)—CH(OH)CH₃; (b) C₁-C₆ alkyl, optionally substituted with one or moresubstituents selected from halogen, cyano, aryl, substituted aryl,heteroaryl, and substituted heteroaryl; (c) C₂-C₆ alkenyl, optionallysubstituted with one or more substituents selected from halogen, cyano,aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and (d)C₂-C₆ alkynyl, optionally substituted with one or more substituentsselected from halogen, cyano, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; W is selected from: (a) C₂-C₆ alkyl containing0, 1, 2, or 3 heteroatoms selected from O, S and N, optionallysubstituted with one or more substituents selected from halogen, cyano,oxo, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; (b)C₂-C₆ alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, Sand N, optionally substituted with one or more substituents selectedfrom halogen, cyano, oxo, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; and (c) C₂-C₆ alkynyl containing 0, 1, 2, or 3heteroatoms selected from O, S and N, optionally substituted with one ormore substituents selected from halogen, cyano, oxo, aryl, substitutedaryl, heteroaryl, and substituted heteroaryl; Z is selected from: (a)hydrogen; (b) halogen; and (c) C₁-C₆ alkyl, optionally substituted withone or more substituents selected from halogen, cyano, aryl, substitutedaryl, heteroaryl and substituted heteroaryl; and R₂′ is hydrogen orR_(p), where R_(p,) is as previously defined.
 2. A compound according toclaim 1 wherein L is ethyl and A, B, W, X, Y, Z and R₂′ are as definedin claim
 1. 3. A compound according to claim 2 wherein X and Y takentogether with the carbon atom to which they are attached are C═O.
 4. Acompound according to claim 1 which is selected from: Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH₂, X and Y takentogether with the carbon atom to which they are attached are C═O, Z isH, and R₂′ is H; Compound of formula I: A and B taken together with thecarbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH(O), X and Y takentogether with the carbon atom to which they are attached are C═O, Z isH, and R₂′ is H; Compound of formula I: A and B taken together with thecarbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡CH, X and Y taken together with the carbon atom to which they areattached are C═O, Z is H, and R₂′ is H; Compound of formula I: A and Btaken together with the carbon atom to which they are attached areC═CH₂, L is CH₂CH_(3,) W is CH₂C≡C-(3-quinolyl), X and Y taken togetherwith the carbon atom to which they are attached are C═O, Z is H, and R₂′is H; Compound of formula I: A and B taken together with the carbon atomto which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NHCH₂-(4-chlorophenyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H; Compoundof formula I: A and B taken together with the carbon atom to which theyare attached are C═CH₂, L is CH₂CH_(3,) W is CH₂C≡CH, X and Y takentogether with the carbon atom to which they are attached are C═O, Z isF, and R₂′ is H; Compound of formula I: A and B taken together with thecarbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH₂NCH₃CH₂-phenyl, X and Ytaken together with the carbon atom to which they are attached are C═O,Z is H, and R₂′ is H; Compound of formula I: A and B taken together withthe carbon atom to which they are attached are C═CH₂, L is CH₃CH_(3,) Wis CH₂CH₂NCH₃CH₂-(2-pyridyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H; Compoundof formula I: A and B taken together with the carbon atom to which theyare attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH₂NCH₃CH₂-(3-pyridyl),X and Y taken together with the carbon atom to which they are attachedare C═O, Z is H, and R₂′ is H; Compound of formula I: A and B takentogether with the carbon atom to which they are attached are C═CH₂, L isCH₂CH_(3,) W is CH₂CH₂NCH₃CH₂-(3-quinolyl), X and Y taken together withthe carbon atom to which they are attached are C═O, Z is H, and R₂′ isH; Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH₂NCH₃CH₂-(2-pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH₂NCH₃CH₂-(3-quinolyl), Xand Y taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H; Compound of formula I: A and B taken togetherwith the carbon atom to which they are attached are C═CH₂, L isCH₂CH_(3,) W is CH₂CH═CH-phenyl, X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H; Compoundof formula I: A and B taken together with the carbon atom to which theyare attached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH-(2-pyridyl), X andY taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H; Compound of formula I: A and B taken togetherwith the carbon atom to which they are attached are C═CH₂, L isCH₂CH_(3,) W is CH₂CH═CH-(3-pyridyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-(5-cyano)pyridyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H; Compoundof formula I: A and B taken together with the carbon atom to which theyare attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(6-(aminocarbonyl)-3-quinolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═CH-(3-quinolyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is F, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂CH═CH-(3-pyridyl), X and Ytaken together with the carbon atom to which they are attached are C═O,Z is F, and R₂′ is H; Compound of formula I: A and B taken together withthe carbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) Wis CH₂C≡CH-phenyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is H, and R₂′ is H; Compound of formula I:A and B taken together with the carbon atom to which they are attachedare C═CH₂, L is CH₂CH_(3,) W is CH₂C═C-(2-pyridyl), X and Y takentogether with the carbon atom to which they are attached are C═O, Z isH, and R₂′ is H; Compound of formula I: A and B taken together with thecarbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═C-(3-pyridyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂C═C-(3-(5-cyano)pyridyl), Xand Y taken together with the carbon atom to which they are attached areC═O, Z is H, and R₂′ is H; Compound of formula I: A and B taken togetherwith the carbon atom to which they are attached are C═CH₂, L isCH₂CH_(3,) W is CH₂C═C-(5-(2-pyridyl)-2-thienyl), X and Y taken togetherwith the carbon atom to which they are attached are C═O, Z is H, and R₂′is H; Compound of formula I: A and B taken together with the carbon atomto which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C═C-(5-(3-pyridinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C═C-(2-pyrimidyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is H, and R₂′ is H; Compoundof formula I: A and B taken together with the carbon atom to which theyare attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C═C-(5-(2-pyridyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is H, and R₂′ is H;Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂CH═C-(6-quinoyl), X and Y taken together with the carbon atom towhich they are attached are C═O, Z is H, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W is CH₂C═C-phenyl, X and Y takentogether with the carbon atom to which they are attached are C═O, Z isF, and R₂′ is H; Compound of formula I: A and B taken together with thecarbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isC₂CH≡C-(2-pyridyl), X and Y taken together with the carbon atom to whichthey are attached are C═O, Z is F, and R₂′ is H; Compound of formula I:A and B taken together with the carbon atom to which they are attachedare C═CH₂, L is CH₂CH_(3,) W is C₂CH≡C-(3-pyridyl), X and Y takentogether with the carbon atom to which they are attached are C═O, Z isF, and R₂′ is H; Compound of formula I: A and B taken together with thecarbon atom to which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C═C-(3-(5-cyano)pyridyl), X and Y taken together with the carbon atomto which they are attached are C═O, Z is F, and R₂′ is H; Compound offormula I: A and B taken together with the carbon atom to which they areattached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridyl)-2-thienyl), X and Y taken together with the carbonatom to which they are attached are C═O, Z is F, and R₂′ is H; Compoundof formula I: A and B taken together with the carbon atom to which theyare attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyrimidyl)-2-thienyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H;Compound of formula I: A and B taken together with the carbon atom towhich they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C≡C-(5-(2-pyridinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H;and Compound of formula I: A and B taken together with the carbon atomto which they are attached are C═CH₂, L is CH₂CH_(3,) W isCH₂C═C-(5-(2-pyrazinyl)-2-pyrrolyl), X and Y taken together with thecarbon atom to which they are attached are C═O, Z is F, and R₂′ is H. 5.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically-acceptable salt,ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier.
 6. A method for controlling a bacterial infection ina subject comprising administering to a subject atherapeutically-effective amount of a pharmaceutically compositionaccording to claim
 5. 7. A method for the preparation of a compound ofFormula I as defined in claim 1 wherein A and B taken together with thecarbon atom to which they are attached are C═CR₁₁R₁ comprising the stepsof: i) reacting a compound represented by the formula

 where L, W, X, Y, R₂′, R_(11,) and R₄″ are as defined in claim 1, witha radical species in the presence of 2,2′-azobisisobutyronitrile,optionally in the presence of a reducing agent in an aprotic solvent atfrom about 40° C. to about 150° C. for from 1 hour to 10 days to providea compound of the formula

 where L, W, X, Y, R₂′, R₄″, R₁₁ and R₁₄ are as defined in claim 1; ii)reacting a compound of step (a) with an acidic solution at from roomtemperature to 100° C. to provide a compound of the formula

 where, L, W, X, Y, R₂′, R₁₁ and R₁₄ are as defined claim 1, iii)oxidizing a compound of step (b) with an oxidizing agent to provide acompound of Formula I, wherein A and B taken together with the carbonatom to which they are attached are C═CR₁₁R₁₄, and where L, W, X, Y, Z,R₂′, R₁₁ and R₁₄ are as defined in claim
 1. 8. A method for preparing acompound of formula I, as defined in claim 1, where A is hydrogen, B is—CHR₁₁R₁₄, comprising the steps of: i) reacting a compound representedby the formula

 where L, W, X, Y, R₂′, R₄″, and R₁₁ are as defined in claim 1, with aradical species in the presence of 2,2′-azobisisobutyronitrile,optionally in the presence of a reducing agent in an aprotic solvent atfrom about 40° C. to about 150° C. for from 1 hour to 10 days to providea compound of formula

 where L, W, X, Y, R₂′, R₄″, R₁₁ and R₁₄ are as defined in claim 1, ii)reacting a compound of step (a) with an acidic solution at from roomtemperature to 100° C. to provide a compound of the formula

 where L, W, X, Y, R₂′, R₁₁ and R₁₄ are as defined in claim 1, ii)oxidizing a compound of step (b) with an oxidizing agent to provide acompound of Formula I, wherein A is hydrogen, B is —CHR₁₁R₁₄, and whereL, W, X, Y, R₂′, R₁₁ and R₁₄ are as defined in claim 1.